Advances in Cancer Biology Research
Over the past year, research projects funded by the Division of Cancer Biology (DCB) have led to many new discoveries and advances in basic cancer research that continue to lay the groundwork for future clinical breakthroughs and cancer prevention strategies. Below are examples of important cancer biology findings.
Cancer Cell Biology
Fortin et al. showed that circadian control of tumor immunosuppression affects the efficacy of immune checkpoint inhibitors in preclinical models. In other words, the findings demonstrated that providing immunotherapy at the time of day when immunosuppressive cells are most abundant significantly enhances the response to treatment. "
Molecular Portrait of Key Driver of Pancreatic Cancer Offers Hope for Continued Treatment Advances
Researchers have established the most comprehensive molecular portrait yet of the workings of KRAS and how its many downstream impacts may influence outcomes for people with pancreatic cancer.
Muta et al. discovered that the cholesterol biosynthetic pathway is selectively activated in serrated colorectal cancers (which are characterized by their invasiveness and resistance to treatment). They also found that cholesterol lowering therapy suppresses tumor growth in preclinical models.
Using genetically engineered pancreatic acinar cells, Xu et al. identified a set of genes with elevated expression during early pancreatic cancer development that may be potential diagnostic biomarkers.
Additional research in this area is supported by the DCB Cancer Cell Biology Branch.
Cancer Immunology, Hematology, and Etiology
LaMarche et al. found that IL-4 signaling in the bone marrow drives the production of immunosuppressive and pro-tumorigenic myeloid cells in non-small cell lung cancer (NSCLC). This data led to a clinical trial testing an IL-4 receptor blocking antibody (i.e., an anti-allergy drug called dupilumab) with immunotherapy in patients with relapsed/refractory NSCLC whose tumors had progressed with immunotherapy alone.
Espinosa-Carrasco et al. showed that intratumoral immune triads (i.e., a three-cell cluster with a dendritic cell simultaneously engaging with a CD8 T cell and a CD4 T cell) are required for effective immunotherapy in preclinical models.
Nuno et al. found that epigenetic mechanisms drive relapse in acute myeloid leukemia (AML).
Additional research in this area is supported by the DCB Cancer Immunology, Hematology, and Etiology Branch.
DNA and Chromosome Aberrations
Cho et al. showed that meiotic recombination 11 (MRE11) is essential for the activation of an innate immune signaling pathway, which is a mechanism that suppresses breast cancer development. When describing the research, Dr. Gaorav Gupta (lead investigator of the study) said, “Our findings suggest that loss of this pathway may be what's allowing breast cancer cells to withstand high levels of DNA damage without being recognized by the immune system.”
Stroik et al. revealed mechanistic details about polymerase theta-mediated end-joining, an error-prone DNA repair pathway that becomes essential when BRCA1 or BRCA2 are mutated.
Using a new digital PCR assay, Rangel et al. found that increased levels of activation-induced cytidine deaminase (an enzyme expressed in B cells) contribute to acute lymphoblastic leukemia health disparities in Latin American populations.
Returning Cancer Cells to an Earlier, More Normal State in Rhabdoid Tumors
According to Dr. Charles W.M. Roberts (lead investigator of the study),“Rather than making a toxic event that kills rhabdoid cancer, we were able to reverse the cancer state by returning the cells toward normal.”
Additional research in this area is supported by the DCB DNA and Chromosome Aberrations Branch.
Biophysics, Bioengineering, and Computational Sciences
By analyzing sequencing data and using computational approaches, Houlahan et al. found that germline-mediated immunoediting shapes breast cancer subtypes and metastatic potential. When describing the work, Dr. Christina Curtis (lead investigator of the study) said, “This new result unearths a new class of biomarkers to forecast tumor progression and an entirely new way of understanding breast cancer origins.”
MuSiCal—A New NCI-Funded Tool for Analyzing Genetic Mutations
Researchers developed the Mutational Signature Calculator (or MuSiCal) that can help determine the underlying cause of genetic mutations.
Mahmood et al. found that mutations in mitochondrial DNA promote a metabolic shift that reshapes the tumor microenvironment to enhance antitumor immunity in melanoma. Additionally, they showed that tumors with mitochondrial DNA mutations are sensitized to immune checkpoint blockade.
Hossain et al. developed PHOENIX, a biologically-informed machine learning approach, to predict genome-wide dynamics.
Additional research in this area is supported by the DCB Biophysics, Bioengineering, and Computational Sciences Branch (BBCSB).
Tumor Biology and Microenvironment
Seeking a Better Biopsy? NCI-Funded Researchers Are Using Machine Learning to Identify Exosome Biomarkers
According to Dr. Raghu Kalluri (lead investigator of the study), “This approach not only means we can detect cancer sooner, and in non-invasive liquid biopsy sources, but it worked across a wide range of cancer types, even identifying tumors of undetermined origins.”
Ye et al. found that senescent cancer-associated fibroblasts (senCAFs) limit Natural Killer cell activity to promote breast cancer progression. They also found that targeting senCAFs enhances antitumor immunity and suppresses breast tumor growth in preclinical models.
Using a multimodal approach, Carpenter et al. identified a cluster of KRT17-high/CXCL8+ intermediary cancer cells with both classical and basal subtype features, which regulate myeloid cell infiltration in the tumor microenvironment. The expression of this cell population could potentially inform the stratification of patients for immunotherapy.
Bhattacharyya et al. found that autotaxin–lysolipid signaling suppresses the accumulation of eosinophils in the tumor microenvironment to promote pancreatic cancer progression.
Additional research in this area is supported by the DCB Tumor Biology and Microenvironment Branch.
Tumor Metastasis
Dashzeveg et al. found that dynamic glycoprotein alterations, specifically the loss of sialylation (i.e., addition of sialic acids), promotes chemotherapy evasion and the metastatic seeding of circulating tumor cell (CTC) clusters in breast cancer. Further, they showed that blocking PODXL (a substrate of a sialyltransferase involved in sialylation) inhibits CTC cluster formation and lung metastasis in preclinical models.
Maji et al. showed that a melanoma differentiation associated gene-9 (MDA-9) signaling pathway mediates prostate cancer cell growth and immunosuppression to promote bone metastasis. They also showed that targeting MDA-9 prevents prostate cancer metastasis in preclinical models.
Gedik et al. found that targeting Transforming Acidic Coiled-Coil Containing Protein (TACC3) induces immunogenic cell death and enhances responses to trastuzumab emtansine (an FDA approved antibody-drug conjugate) to overcome therapeutic resistance in preclinical models of HER2-positive breast cancer.
Additional research in this area is supported by the DCB Tumor Metastasis Branch.
DCB Research Programs
Heiser et al. with the Human Tumor Atlas Network (HTAN) generated a spatial-omic atlas of colorectal cancer, which revealed why these types of tumors evade the immune system. This resource could potentially be used to inform patient stratification and the development of effective therapies for colorectal tumors.
Fabiano et al. with the Cancer Tissue Engineering Collaborative (TEC) developed a multiplex, high-throughput approach to study circulating cancer and immune cell mechanotransduction. When describing the new system, Dr. Michael King (lead investigator of the study) said, “We hope that this new method for performing higher throughput mechanobiology research on suspended cells will be useful to the research community.”
Leibold et al. with the Oncology Models Forum (OMF) developed electroporation-based genetically engineered mouse models (EPO-GEMM) of gastric cancer, which revealed genotype-specific features of metastatic disease. These preclinical models can be used to advance the understanding of how gastric cancers evolve, spread and respond to therapy.
DCB research programs supported these studies, as well as foster emerging areas and model development in cancer biology.