Connect with us

Uncategorized

Rewired Mitochondria Help Mice Boost Immune Response to Tumors

Salk Institute scientists found that manipulating an early step in energy production in mitochondria reduces melanoma tumor growth and enhances immune…

Published

6 months ago

on

Immunotherapy, which uses the body’s own immune system to fight cancer, can be an effective treatment option, yet many patients do not respond to it. Cancer researchers are seeking new ways to optimize immunotherapy so that it might be more effective for more people.

It has previously been thought that cancer cells do not rely heavily on mitochondria, despite still having oxygen and sugars available to them to fuel mitochondrial metabolism. This hypothesis dominated the field of cancer metabolism until recently, when scientists found that mitochondria actually do play multiple important roles in tumor growth.

Kaech and co-senior study author Gerald Shadel, PhD, teamed up to better understand how mitochondria influence both tumor growth and the way in which the immune system recognizes and responds to cancer. Shadel holds the Audrey Geisel Chair in Biomedical Science, and director of the San Diego Nathan Shock Center of Excellence in the Basic Biology of Aging.

“We wanted to better understand how tumors acquire the metabolic state that gives them a growth advantage as well as an ability to evade the immune system, which I call the ‘double whammy,’” said Susan Kaech, PhD, director of the NOMIS Center for Immunology and Microbial Pathogenesis.  “And we found a way to make the tumors more recognizable by the immune system and potentially more responsive to immunotherapy.” Kaech is co-senior author of the researchers’ published paper in Science, titled “Manipulating mitochondrial electron flow enhances tumor immunogenicity.” In their paper the team concluded, “… this ETC-rewiring approach might represent a one-two punch to convert cold tumors to hot and to improve antitumor responses and immunotherapy efficacy.”

From left: Susan Kaech, Karthik Varanasi, Kailash Chandra Mangalhara, and Gerald Shadel. [Salk Institute]

For their study, the investigators altered a key step in the electron transport chain, the process that moves electrons through mitochondria, and which ultimately leads to production of adenosine phosphate (ATP), the main energy-providing molecule in cells.

There are two primary routes by which electrons flow inside mitochondria to initiate ATP production. The “gatekeepers” for these two routes are known as complex I (CI) and complex II (CII). As the team explained in their paper, “Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear.”

To investigate the contributions of CI and CII to tumor growth and antitumor responses the team knocked out either CI or CII in mouse melanoma cells, that were then implanted into experimental mice.

They observed that tumors in which CII, but not CI, was knocked out were more slow growing. “Unexpectedly, CI and CII knockout had notably differential effects on tumor growth …” the team noted. “.… CII knockout tumors grew significantly slower compared with control and CI knockout tumors.” Significantly, CII knockout tumors also showed increased immune cell infiltration, especially CD8+ immune cells, relative to control and CI knockout tumors.

A mouse melanoma tumor showing blood vessels (red), MHC proteins (blue), and an infiltration of specialized immune cells (green).
A mouse melanoma tumor showing blood vessels (red), MHC proteins (blue), and an infiltration of specialized immune cells (green). [Salk Institute]

Further investigation showed that knocking out CII and so forcing electrons to primarily go through just one of the ETC routes led to overproduction of the metabolite succinate. This accumulation of succinate led to expression of immune genes in the nucleus and increased the levels of a protein called MHC on the surface of the tumor cells. “We found significantly higher MHC-I expression on CII knockout tumor cells compared with CI knockout and control tumor cells in vivo,” they wrote. In turn, elevated levels of MHC made the tumor cells more visible to the specialized killer T immune cells that recognize and eliminate cancer cells.

While the team knew that the metabolic state of tumor cells dictated their enhanced growth properties, this new finding shows that relatively simple manipulations to mitochondrial electron transport can convert a tumor that is evading immune detection into one that is now highly susceptible to immune system attack. “There’s an explosion of recent research activity from my lab and others revealing how mitochondria regulate the immune system and inflammation, and this study highlights an exciting new chapter in this story,” said Shadel.

The authors added, “… we conclude that the loss of CII, but not of CI, results in a strong antitumor T cell response through increased antigen presentation.” The collective results indicate that increasing intracellular tumor succinate and MHC-1 by inhibiting CII enhances tumor cell immunogenicity and the activation and infiltration of tumor-reactive CD8+ T cells that suppress tumor growth. “Our results indicate that discrete rewiring of the ETC to moderately reduce CII activity or increase succinate in tumors not only improves T cell engagement by increasing MHC-I but also enhances the selective expansion of protective T cell clones, which suggests that tumor MHC-I levels determine tolerogenic versus immunogenic set points for tumor antigens.”

“We were surprised to find that mitochondrial activity determines how susceptible a tumor is to being recognized by the immune system,” commented co-first author Kailash Chandra Mangalhara, PhD, a senior research associate in Shadel’s lab. We think we found a novel mechanism by which antigen presentation in tumor cells is regulated. These findings change how we now think about future treatment strategies.”

The researchers plan to explore ways to leverage the newly identified mechanism to fight cancer without harming mitochondria, which can have adverse effects on normal cells. They will continue to study the role of mitochondrial metabolism in cancer, immune responses, and immunotherapy efficacy.

The post Rewired Mitochondria Help Mice Boost Immune Response to Tumors appeared first on GEN - Genetic Engineering and Biotechnology News.

Read More

Related Topics:
Continue Reading

Uncategorized

Analyst revamps MicroStrategy stock price target after Bitcoin buy

Here’s what could happen to MicroStrategy shares next.

Published

3 hours ago

on

March 20, 2024

By

How does Michael Saylor feel about bitcoin? We'll let him tell you in his own words.

"Bitcoin is a swarm of cyberhornets serving the goddess of wisdom, feeding on the fire of truth, exponentially growing ever smarter, faster, and stronger behind a wall of encrypted energy," the executive chairman and co-founder of MicroStrategy  (MSTR)  once said.

Too subtle? Still not sure how the former CEO of the software intelligence company feels about the world's largest cryptocurrency? 

Maybe this will help.

"Bitcoin is a bank in cyberspace, run by incorruptible software, offering a global, affordable, simple and secure savings account to billions of people that don't have the option or desire to run their own hedge fund," Saylor said.

Okay, so the guy really likes bitcoin. And on March 19, the first day of spring, MicroStrategy took a bigger bite out of bitcoin when the company said it had bought 9,245 bitcoins for $623 million between March 11 and March 18.

MicroStrategy said it a completed a $603.75 million convertible debt offering — its second in a week — to raise money to buy bitcoin.

The company now holds about $13.5 billion of bitcoin, which adds up to more than 1% of the 21 million bitcoin that will ever exist, according to CoinDesk.

An analyst adjusts his price target for MicroStrategy

shutterstock

Committed to developing bitcoin network

MicroStrategy said in a regulatory filing that it had paid roughly $7.53 billion for its bitcoin stash, an average of $35,160 per coin.

The company's stock fell on Tuesday, while bitcoin posted its biggest single-day loss since November 2022. MicroStrategy was off slightly to $1,416 at last check on Wednesday and bitcoin was up 2.3% to $63.607.

Related: Analyst unveils Nvidia stock price 'line in the sand'

Phong Le, MicroStrategy’s president and CEO, told analysts during the company’s Feb. 6 fourth-quarter-earnings call that "we remain highly committed to our bitcoin strategy with a long-term focus.."

"We consider MicroStrategy to be the world's first bitcoin development company," he said. "We are a publicly traded operating company committed to the continued development of the bitcoin network through activities in the financial markets, advocacy, and technology innovation."

MicroStrategy earned $4.96 a share in the quarter, beating the FactSet consensus of a loss of 64 cents, and light years beyond the year-ago loss of $21.93 a share.

Revenue totaled $124.5 million, compared with FactSet's call for $133 million and the year-earlier tally of $132.6 million.

During the call, Saylor told analysts that "2024 is the year of birth of bitcoin as an institutional-grade asset class."

MicroStrategy, he said, completed the first 15 years of the bitcoin life cycle, back when it was largely unregulated and misunderstood. 

"The next 15 years, I would expect, will be a regulated, institutional, high-growth period of bitcoin, very, very different in many ways from the last 15 years," Saylor said.

Crypto's dark days

"Bitcoin itself is performing well for a number of reasons, but one reason is because it represents the digital transformation of capital," he added.

Of course, life with bitcoin wasn't always sunshine and roses. 

More Wall Street Analysts:

We take you back now to those less-than-thrilling days yesteryear, when covid-19 was on the rampage and the price of bitcoin fell 30% from March 8 to March 12 2020.

By the end of 2021, bitcoin had fallen nearly 30%. And 2023 saw the cryptocurrency sector wracked with bankruptcy and scandal, with the likes of FTX CEO Sam Bankman-Fried being convicted of fraud, conspiracy, and money laundering. 

SBF, as he has been known, is scheduled to be sentenced in Manhattan federal court on March 28. He faces a long stretch.

But bitcoin rose about 160% in 2023 and hit a record $73,750 on March 14.

Saylor recently said that his high hopes for bitcoin this year stemmed largely from the U.S. Securities and Exchange Commission approving spot bitcoin ETFs and the upcoming bitcoin halving, where when bitcoin's mining reward is split in half.

MicroStrategy is the first bitcoin development company, Saylor told analysts, but perhaps not for long. 

"We've published our playbook, and we're showing other companies how to do it," he said.

TD Cowen analyst Lance Vitanza cited MicroStrategy's latest bitcoin acquisition when he adjusted his price target for the company's shares on March 20.

The analyst cut the investment firm's price target on MicroStrategy to $1,450 from $1,560 and affirmed an outperform rating on the shares. 

He says the shares remain an attractive vehicle for investors looking to gain bitcoin exposure.

Related: Veteran fund manager picks favorite stocks for 2024

Read More

Continue Reading

Uncategorized

FoxO6-mediated ApoC3 upregulation promotes hepatic steatosis and hyperlipidemia in aged rats fed a high-fat diet

“This discovery unveils a potential novel molecular target for therapeutic strategies against hepatic steatosis during the aging process […]” Credit:…

Published

6 hours ago

on

March 20, 2024

By

“This discovery unveils a potential novel molecular target for therapeutic strategies against hepatic steatosis during the aging process […]”

Credit: 2024 Kim et al.

“This discovery unveils a potential novel molecular target for therapeutic strategies against hepatic steatosis during the aging process […]”

BUFFALO, NY- March 20, 2024 – A new research paper was published in Aging (listed by MEDLINE/PubMed as “Aging (Albany NY)” and “Aging-US” by Web of Science) Volume 16, Issue 5, entitled, “FoxO6-mediated ApoC3 upregulation promotes hepatic steatosis and hyperlipidemia in aged rats fed a high-fat diet.”

FoxO6, an identified factor, induces hyperlipidemia and hepatic steatosis during aging by activating hepatic lipoprotein secretion and lipogenesis leading to increased ApoC3 concentrations in the bloodstream. However, the intricate mechanisms underlying hepatic steatosis induced by elevated FoxO6 under hyperglycemic conditions remain intricate and require further elucidation.

In this new study, researchers Dae Hyun Kim, Seulah Lee, Sang Gyun Noh, Jaewon Lee, and Hae Young Chung from Pusan National University aimed to delineate the regulatory pathway involving ApoC3 controlled by FoxO6 and its resultant functional impacts.

“[…] we employed a spectrum of models including liver cell cultures, aged rats subjected to HFD, transgenic mice overexpressing FoxO6 (FoxO6-Tg), and FoxO6 knockout mice (FoxO6-KO).”

Their findings indicate that FoxO6 triggered ApoC3-driven lipid accumulation in the livers of aged rats on an HFD and in FoxO6-Tg, consequently leading to hepatic steatosis and hyperglycemia. Conversely, the absence of FoxO6 attenuated the expression of genes involved in lipogenesis, resulting in diminished hepatic lipid accumulation and mitigated hyperlipidemia in murine models. Additionally, the upregulation of FoxO6 due to elevated glucose levels led to increased ApoC3 expression, consequently instigating cellular triglyceride mediated lipid accumulation. The transcriptional activation of FoxO6 induced by both the HFD and high glucose levels resulted in hepatic steatosis by upregulating ApoC3 and genes associated with gluconeogenesis in aged rats and liver cell cultures.

“Our conclusions indicate that the upregulation of ApoC3 by FoxO6 promotes the development of hyperlipidemia, hyperglycemia, and hepatic steatosis in vivo, and in vitro. Taken together, our findings underscore the significance of FoxO6 in driving hyperlipidemia and hepatic steatosis specifically under hyperglycemic states by enhancing the expression of ApoC3 in aged rats.”
 

Read the full paper: DOI: https://doi.org/10.18632/aging.205610 

Corresponding Author: Hae Young Chung

Corresponding Email: hyjung@pusan.ac.kr 

Keywords: HFD-feeding, aging, forkhead transcription factor O6, ApoC3, lipid accumulation, hepatic steatosis

Click here to sign up for free Altmetric alerts about this article.

 

About Aging:

Aging publishes research papers in all fields of aging research including but not limited, aging from yeast to mammals, cellular senescence, age-related diseases such as cancer and Alzheimer’s diseases and their prevention and treatment, anti-aging strategies and drug development and especially the role of signal transduction pathways such as mTOR in aging and potential approaches to modulate these signaling pathways to extend lifespan. The journal aims to promote treatment of age-related diseases by slowing down aging, validation of anti-aging drugs by treating age-related diseases, prevention of cancer by inhibiting aging. Cancer and COVID-19 are age-related diseases.

Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

Please visit our website at www.Aging-US.com​​ and connect with us:

  • Facebook
  • X, formerly Twitter
  • Instagram
  • YouTube
  • LinkedIn
  • Reddit
  • Pinterest
  • Spotify, and available wherever you listen to podcasts

 

Click here to subscribe to Aging publication updates.

For media inquiries, please contact media@impactjournals.com.

 

Aging (Aging-US) Journal Office

6666 E. Quaker Str., Suite 1B

Orchard Park, NY 14127

Phone: 1-800-922-0957, option 1

###

Journal

Aging-US

DOI

10.18632/aging.205610

Method of Research

Experimental study

Subject of Research

People

Article Title

FoxO6-mediated ApoC3 upregulation promotes hepatic steatosis and hyperlipidemia in aged rats fed a high-fat diet

Article Publication Date

3-Mar-2024

Read More

Continue Reading

Uncategorized

ARPA-H appoints Etta Pisano to lead its Advancing Clinical Trials Readiness Initiative

The Advanced Research Projects Agency for Health (ARPA-H) has appointed Etta D. Pisano, MD, FACR, senior portfolio lead, to build the agency’s clinical…

Published

10 hours ago

on

March 20, 2024

By

The Advanced Research Projects Agency for Health (ARPA-H) has appointed Etta D. Pisano, MD, FACR, senior portfolio lead, to build the agency’s clinical trial portfolio and lead the ARPA-H Advancing Clinical Trials Readiness Initiative under ARPA-H Resilient Systems Mission Office Director Jennifer Roberts.

Credit: N/A

The Advanced Research Projects Agency for Health (ARPA-H) has appointed Etta D. Pisano, MD, FACR, senior portfolio lead, to build the agency’s clinical trial portfolio and lead the ARPA-H Advancing Clinical Trials Readiness Initiative under ARPA-H Resilient Systems Mission Office Director Jennifer Roberts.

The first radiologist to be appointed to such a role, Dr. Pisano is an internationally recognized expert in women’s health, breast cancer research, and the use of artificial intelligence in medical imaging applications.

“I am honored to be working for ARPA-H to identify and promote research that can improve healthcare quality, efficacy and delivery, and to improve patient care and access to clinical trials for all Americans, including women, rural residents, and the underserved,” said Dr. Pisano.

Dr. Pisano will continue to serve as study chair of the large-scale Tomosynthesis Mammographic Imaging Screening Trial (TMIST) for the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN). TMIST is led by ECOG-ACRIN with funding from the National Cancer Institute, part of the National Institutes of Health. She will also continue to serve as the American College of Radiology® (ACR®) Chief Research Officer (CRO). Dr. Pisano previously served as the principal investigator of the landmark Digital Mammographic Imaging Screening Trial (DMIST).

The TMIST breast cancer screening study is among the fastest growing National Cancer Institute (NCI) trials of the COVID-19 era. Under Dr. Pisano’s leadership, TMIST is assembling one of the most diverse cancer screening trial populations ever. Approximately 21% of TMIST U.S. participants are Black—more than double the average rate for Black participation in NCI-funded clinical trials (9%).

With ARPA-H, Dr. Pisano will work to build underserved and minority participation in clinical trials—including identifying and onboarding rural facilities and those outside of large academic medical centers—such as emerging retail healthcare sites. 

These duties are also very consistent with the missions of ECOG-ACRIN and ACR, which include promoting the exploration and identification of next-generation technologies that can benefit patients and providers.

“This is a great opportunity for Etta, and I’m excited about the impact she will make on our approach to clinical trials,” said Mitchell D. Schnall, MD, PhD, group co-chair of ECOG-ACRIN.

About ECOG-ACRIN

The ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) is an expansive membership-based scientific organization that designs and conducts cancer research involving adults who have or are at risk of developing cancer. The Group comprises nearly 1400 member institutions and 21,000 research professionals in the United States and around the world. ECOG-ACRIN is known for advancing precision medicine and biomarker research through its leadership of major national clinical trials integrating cutting-edge genomic approaches. Member researchers and advocates collaborate across more than 40 scientific committees to design studies spanning the cancer care spectrum, from early detection to management of advanced disease. ECOG-ACRIN is funded primarily by the National Cancer Institute, part of the National Institutes of Health. Visit ecog-acrin.org, and follow us on X @eaonc, Facebook, LinkedIn, and Instagram.

Media Contact: Diane Dragaud, Director of Communications, communications@ecog-acrin.org.

Read More

Continue Reading

Trending