Harnessing Cancer Metabolomics to Transform Therapeutic Discovery

A Massachusetts General Hospital research team is among the inaugural winners of a Breakthrough Award from the Krantz Family Center for Cancer Research. Their project, "Revolutionizing cancer metabolism studies for enhanced therapeutics," exemplifies the award's aim to drive innovative research and discovery that produce fundamental changes in cancer treatment.

Subscribe to the latest updates from Cancer Center Advances in Motion

Thank you for subscribing!

Error: Please enter a valid email address.

Email Address Submit

"The ambition of this project is to support an emerging field of research targeting a particularly aggressive and lethal cancer for which treatment remains elusive," says Nabeel Bardeesy, PhD, an associate investigator in the Krantz Family Center for Cancer Research at Mass General. "This work will build on discoveries that are rapidly transforming our understanding of cancer metastasis and offering insight into novel therapeutic approaches to an intractable disease."

The Unique Challenges of Aggressive Cancer

Pancreatic ductal adenocarcinoma (PDAC) accounts for approximately 90% of pancreatic cancers. Its aggressiveness translates to a 5-year survival rate as low as 10%, largely attributable to the difficulty of early diagnosis. Up to 90% of PDAC patients are diagnosed at an advanced stage that prevents tumor resection as a treatment option.

Many solid tumors create their own vasculature to support proliferation by delivering sufficient nutrients and oxygen to the tumor microenvironment (TME). However, the TME of pancreatic tumors presents a unique architecture of connective tissue that prevents angiogenesis, creates an immunosuppressive barrier, and prevents the delivery of different therapies.

This requires PDAC tumor cells to support their growth and survival in an environment that prevents both.

"What originally brought Dr. Bardeesy and me together was that our independent investigations into how pancreatic cancer adapts to these conditions converged on results that pointed to similar pathways," explains Raul Mostoslavsky, MD, PhD, scientific director of the Krantz Family Center for Cancer Research. Their findings revealed that these cancer cells recalibrate different metabolic pathways to promote their survival under different conditions.

Adapt and Survive

Mutations in the KRAS oncogene predominantly drive PDAC initiation and metastasis. Although clinical trials of KRAS-targeted therapies show promise, the broad scope of what KRAS controls and how cells adapt to its inhibition makes it a challenging therapeutic target. Among KRAS-regulated pathways are those involved in cellular metabolism.

Normal cells generate energy through oxidative phosphorylation (OXPHOS) driven by mitochondria in a highly efficient process that uses its own byproducts as fuel. In cancer cells, mutations that cause metabolic reprogramming shift energy creation toward other pathways, such as glycolysis. Although less efficient, these pathways also generate byproducts that are important to maintaining other processes that are key to cell survival.

Among these byproducts, lactate can be secreted from cancer cells to create an increasingly hypoxic and acidic TME inhospitable to normal cells. This drives additional fine-tuning of signaling pathways and gene transcription to ensure that the cancer cells thrive in a nutrient-deficient TME calibrated exclusively for their survival. These pathways include those focused on:

• Nutrient scavenging: Acquisition of intracellular and extracellular macromolecules that can be used to sustain rapid cell growth and energy production
• Extracellular signaling: Recruitment and "reprogramming" of non-cancerous cells to allow their survival within the TME to support tumor growth

Metabolic reprogramming is a central hallmark of cancer adaption, with multiple pathways utilized and regulated in a tightly controlled and highly dynamic fashion. It is also implicated in therapeutic resistance and manipulation of immune cell populations and activities within the TME. These observations challenge a previously accepted hypothesis that genetics drive cancer's ability to adapt and metastasize.

"Studies show that cells from the primary tumor and metastatic lesions present almost identical genomic profiles," Dr. Bardeesy explains. "However, evidence of distinct non-genetic adaptations observed within these cells suggests that the difference lies in how their respective metabolic profiles evolve to support survival at a given destination."

Establishing Models of Metastatic Adaption

Among patients with PDAC tumors eligible for surgical resection, approximately 80% present evidence of distant metastases and subsequently experience recurrence. "The metastatic mechanisms related to this disease remain a black box," says Dr. Bardeesy. "We believe that metabolomic profiling could be the key that opens it."

The goals outlined in their proposal include creating the infrastructure necessary to support cancer metabolomics research, generating novel PDAC models, and identifying potential metabolic targets for therapies. This includes establishing a foundational understanding of how PDAC mutations initiate metabolic reprogramming and the resulting environmental changes that drive tumor adaptation and metastasis.

"To identify possible drivers of metastatic growth, it's necessary to start with a well-defined experimental system capable of revealing how things work at a fundamental level," advises Dr. Mostoslavsky. "Tumor heterogeneity between patients or even within the same patient makes clinical samples poor models for this type of discovery."

To address this, both laboratories established genetically engineered mouse models with common genetic backgrounds and intact immune systems (i.e., syngeneic mice). These mice enable:

• Establishment of a primary tumor harboring specific mutations
• Isolation of the tumor cells for in vitro expansion or manipulation
• Implantation of the cells in mice with the same genetic background, which avoids post-transplant immune responses or allograft rejection
• Consistent in vivo reproduction of the same primary tumor, TME, and metastatic processes

Preliminary data generated using these models identified a group of metabolic genes selectively upregulated in cells from a metastatic lesion but not from the primary tumor. Their analysis revealed that one of these genes encodes an enzyme involved in host-tissue remodeling that creates a scaffold supportive of cell growth. This is similar to the remodeling that occurs during the establishment of a pre-metastatic niche and TME to support invading tumor cells. They subsequently corroborated these findings in patient-derived samples from metastatic and primary PDAC tumors.

"These models enable the discovery of how different mutations drive metabolic changes in different physiological contexts, as well as the effect of different therapeutic interventions," says Dr. Bardeesy. The models also allow investigation of these processes in vivo, which is the only context relevant to how metastasis actually occurs. "What we learn using these models informs and clarifies what we need to look for in patient samples."

A Place Built for Breakthroughs

Both investigators acknowledge that this project is driven by recognizing the necessity to develop complex techniques to grow what could be a transformative approach to cancer research. This ambition extends to establishing a pipeline capable of supporting in vivo metabolomics research.

They also agree that the atmosphere surrounding Mass General makes even the most ambitious of goals appear achievable. "There are currently very few places capable of these types of investigations, making time-sensitive research to iteratively test a given hypothesis in this field challenging or impossible," explains Dr. Bardeesy. "Our access to amazing resources and collaborators affords us a rare opportunity to accomplish something transformative."

The award will foster the development of models, methods, and infrastructure of immediate benefit to not only their research but also that of other investigators looking for answers to the same difficult questions. Dr. Mostoslavsky offers "enabling" as a one-word description of the award's potential far-reaching impact.

"Awards like this support pushing boundaries and testing ideas to overcome seemingly insurmountable problems," he says. "Our success will enable that of others and hopefully create the momentum required for future breakthroughs."

Learn more about the Krantz Family Center for Cancer Research

Learn more about Mass General Cancer Center