The Biology Of Cancer 3rd

[Shelly Takacs]

Virtuallyall major advances against cancer originated with discoveries in basic science. Basic research can reveal new ideas about the causes of cancer and how it develops, progresses, and responds to therapy.

Knowledge gained from such studies deepens our understanding of cancer and produces insights that could lead to new clinical interventions. For example, studies of cell signaling pathways in normal cells and cancer cells have contributed greatly to our knowledge about the disease, revealing molecular alterations that are shared among different types of cancer and pointing to possible treatment strategies.

Federal funding for cancer biology is essential because this area of research receives relatively little funding from entities that are driven by profit. NCI supports and directs cancer biology research through a variety of programs and approaches. For example:

The Division of Cancer Biology (DCB) supports basic research in all areas of cancer biology at academic institutions and research foundations across the United States. As part of the National Cancer Institute, DCB provides funding for research that investigates the basic biology behind cancer.

Research in the field of basic cancer biology focuses on the mechanisms that underlie fundamental processes such as cell growth, the transformation of normal cells to cancer cells, and the spread, or metastasis, of cancer cells. This research provides the building blocks to new treatments, clinical trials, and improved understanding of the disease. Basic research has enabled much of the progress made over the years in the search for a cure for cancer.

Cancer describes an enormous spectrum of diseases that all originate from uncontrolled cellular growth. Broadly divided into benign tumors (unable to metastasize) or malignant tumors (able to invade normal tissues), cancers are further defined and classified by their cell type, tissue, or organ of origin. Cancer remains the number two cause of death in the U.S., second only to heart disease, and the Intramural Research Program (IRP) is committed to advancing research, building expertise, and leveraging resources to address this global challenge. Our scientists are constantly learning more about the causes of cancer, and developing new and better ways to prevent, detect, and treat it.

IRP cancer research encompasses an incredible diversity of disciplines, from population epidemiology, basic research and drug discovery, through the drug development process, to clinical trials conducted both nationwide and at the NIH Clinical Center. Our broad areas of cancer research include:

The promise of precision medicine lies in the ability to target molecular pathways driving specific cancers. We investigate the basic functioning of these pathways and use discoveries to develop new and more effective cancer diagnostics and precision therapies.

The Department of Cancer Biology performs lab-based research investigating the molecular pathways driving cancer. We use discoveries about the basic functioning of these pathways to develop novel cancer diagnostics and precision treatments.

A major challenge for cancer therapy is the generation of medicines that kill cancer cells while leaving normal cells unharmed. The promise of precision medicine lies in the ability to target the molecular pathways specific to individual cancer types.

Under the leadership of Department Chair Bradley Bernstein, MD, PhD, our 25 independent faculty and more than 300 laboratory personnel combine structural, chemical, genetic, computational, and biochemical approaches to identify molecular vulnerabilities unique to cancer cells, and to generate novel compounds with therapeutic potential.

Members of our department investigate the disruption of the molecular pathways governing growth, leading to cancer. Our discoveries provide the basis for new therapies that target molecular defects in specific cancers and help to improve immune system targeting of tumors.

Macromolecules perform critical functions in cells. We conduct studies to determine the three-dimensional structures of cancer-associated molecules, how these structures are formed, and how structural alterations affect function.

The regulation of energy intake and utilization at the cellular and organismic level is of profound importance to human health. We use a combination of biochemical, genetic, and computational techniques to define key molecules and metabolic pathways.

The interdepartmental program leading to the PhD in Cancer Biology combines training in the basic biomedical sciences with opportunities to apply clinical and translational research to studies on human cancer.

Drs. Schlessinger and Lemmon are committed to building an institute for the long term and with a clear emphasis on making their research count for cancer. In concert with Yale Cancer Center, the Institute aims to become a driver of basic science through opportunities emerging from clinical research already at Yale.

Jared won the best student graduate poster at the 23rd Annual Retreat for Cancer Biology! His research in Goldenring Lab examines fibroblasts and how they have recently been shown to promote the dysplastic transition of metaplastic lineages in the stomach. Specifically, conditioned media (CM) from gastric metaplasia and cancer-derived fibroblasts accelerated dysplastic progression in metaplastic gastroids. It remains unclear which factors secreted from fibroblasts cause this progression. Therefore, he performed scRNA-sequencing on normal, metaplasia, and cancer-derived fibroblasts. This revealed expression differences of many secreted factor encoding genes. Metaplastic gastroids were cultured in 30 and 50 kDa filtered CM from cancer-derived fibroblasts to narrow down candidate factors. 30 kDa filtrate CM enhanced dysplastic progression of metaplastic gastroids compared to 50 kDa filtrate. Therefore, they looked specifically for genes encoding 30 kDa or fewer proteins and found high SPON2 expression only in metaplasia and cancer-derived fibroblasts. SPON2 is a 30 kDa secreted protein shown to promote the proliferation and migration of gastric cancer cells. Therefore, they hypothesize that fibroblasts secrete SPON2 to induce dysplasia. The presence of SPON2 in CM was confirmed with mass spectrometry, detecting SPON2 only in metaplasia and cancer-derived fibroblast CM. Furthermore, STAT3 inhibition was evaluated because SPON2 has been shown to promote downstream signaling through STAT3. A STAT3 inhibitor suppressed the effect of cancer-derived fibroblast CM in the dysplastic progression of metaplastic gastroids. These are the first studies investigating fibroblast-derived SPON2 in the induction of precancerous gastric dysplasia. Understanding factors that contribute to gastric dysplasia represents an important area of research, as gastric cancer remains one of the leading causes of cancer-related deaths worldwide.

Erik graduated in December of 2023 after successfully defending and publishing his research entitled Bioinformatics Screen Reveals Gli-Mediated Hedgehog Signaling as an Associated Pathway to Poor Immune Infiltration of Dedifferentiated Liposarcoma in the journal Cancers.

We are pleased that Erik will continue working with VUMC as a postdoctoral researcher in his thesis laboratory to wrap up a few publications while preparing for the next steps in his career.

Congratulations to Ebony Hargrove-Wiley for starting a new position as Future Leaders Advancing Research in Endocrinology (FLARE) Fellow at the Endocrine Society. The Endocrine Society unites, leads, and grows the community to accelerate scientific breakthroughs and improve health worldwide. We are unique in that our 18,000 members from 119 countries are not only on the frontier of breakthrough research discoveries, but they also apply this knowledge in treating patients with hundreds of debilitating hormone-related diseases and conditions such as diabetes, obesity, osteoporosis, thyroid disorders, and infertility.

Ebony will receive leadership training through a workshop led by the Endocrine Society in addition to academic and professional mentorship from an expert endocrinologist. She hopes to gain knowledge and skills to advance her research which focuses on sex differences in breast cancer immunity.

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The mission of the Department of Cancer Biology is to build bridges and teams to drive the best ideas in basic and translational cancer biology and developmental therapeutics to achieve breakthrough advances in the prevention, treatment and cure of cancer.

The department faculty are international leaders in brain, colorectal and prostate cancers, leukemia and myeloma, as well as cancer stem cells, mechanisms of DNA damage and repair, and fundamental molecular and cellular processes that impact microbial infections and cancer. Identifying the molecular mechanisms involved in the development and progression of human cancers as well as in normal cellular regulatory processes is our goal, enabling us to achieve our long-term objective of rapidly translating research into strategies that improve patient outcomes.

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