An expanded universe of cancer targets

Abstract

The characterization of cancer genomes has provided insight into somatically altered genes across tumors, transformed our understanding of cancer biology, and enabled tailoring of therapeutic strategies. However, the function of most cancer alleles remains mysterious, and many cancer features transcend their genomes. Consequently, tumor genomic characterization does not influence therapy for most patients. Approaches to understand the function and circuitry of cancer genes provide complementary approaches to elucidate both oncogene and non-oncogene dependencies. Emerging work indicates that the diversity of therapeutic targets engendered by non-oncogene dependencies is much larger than the list of recurrently mutated genes. Here we describe a framework for this expanded list of cancer targets, providing novel opportunities for clinical translation.

Figure 1.. Categories of cancer targets.

Recent studies have identified an expanded universe of cancer targets that include both tumor intrinsic targets and extrinsic targets including components of the tumor microenvironment. Among growing number of emerging targets (in green), the concept of oncogenic cell states captures the multi-dimensional complexity of a tumor with dynamic transition states, underlying regulatory mechanisms, and subpopulation-dependent plasticity that defines cellular phenotype and therapeutic response. These new targets are the consequence of tumor heterogeneity and represent non-oncogene-dependent cancer vulnerabilities, which inform new types of therapeutic opportunities.

Figure 2:. Oncogenic targets and cell states.

This schematic represents the coexistence of distinct, yet isogenic malignant cell states within a tumor, each one presenting an equally distinct repertoire of non-oncogene dependencies. To avoid cluttering, tumor microenvironment-related cell states are not shown, even though they are involved in critical paracrine interactions with tumor cells. (A) Schematic representation of isogenic tumor cells presenting with distinct transcriptional states and epigenetic profiles. These include: (i) a low-proliferative (i.e., quiescent) meta-stable stem-like progenitor cell state capable of self-renewal and asymmetric differentiation (ii) two stable, differentiated cell states, persisting for long time periods, associated with either an epithelial (proliferative) or a mesenchymal (quiescent) cell phenotype, and (iii) an additional neuroendocrine (quiescent) stable state that can only be achieved by drug-induced transdifferentiation. The size of the arrows illustrates the likelihood of transition from one cell state to another. Stem-like progenitors can differentiate into either epithelial or mesenchymal cells, which can plastically reprogram between these states, albeit at different rates, for instance as a result of epithelial mesenchymal transformation processes. The neuroendocrine state is not pathophysiologically accessible but can be reached via drug-mediated transdifferentiation from the epithelial cell state. (B) Schematic representation of the canalization entropy landscape that underlies the possible cell states. Cells tend to move from a higher to a lower entropy state with a probability that is inversely proportional to the entropic barrier that separates them DE1 (i.e., height of the peak separating two adjacent valleys) and directly proportional to their differential entropy DE2 (i.e. differential depth of two adjacent valleys). For instance, an epithelial state cell can reprogram to a mesenchymal state cell because the entropic barrier between the two is low (plasticity) but the forward direction is more likely than the reverse one because the entropy of the mesenchymal state is lower. (C) Schematic representation of the tumor composition changes following drug treatment or spontaneous progression. For simplicity, only four transitions are illustrated, including: (i) Metastatic progression, associated with an increased ratio of mesenchymal to epithelial cells but no change in the fraction of stem-like progenitors, (ii) Chemotherapy treatment, resulting in ablation of the proliferative epithelial state and increase of the stem-like progenitor and mesenchymal quiescent states, (iii) Targeted Therapy A, inducing reduction of the stem-like progenitor and mesenchymal quiescent states and increase of the epithelial proliferative state, and (iv) Targeted Therapy B, resulting in the emergence of a novel neuroendocrine state resulting from drug-induced transdifferentiation.

Figure 3.. Tumor microenvironment targets.

(A) Tumors are composed of a complex mixture of cancer cells in genetically and phenotypically distinct cell states surrounded by a fibrillar extracellular matrix and a diverse fibroblastic and immune stroma. Current therapies target VEGF to inhibit angiogenesis, disrupt T-cell immune checkpoints with antibody based immunotherapy, disrupt survival signaling pathways that are mediated by cancer associated fibroblasts, and deliver engineered immune cells to eliminate cancer cells. Our understanding of the molecular basis of interactions among cell types remains incomplete and therefore new methods are required to understand the individual and collaborative functions of these various cell populations. (B) Recent technical advances enable primary and metastatic tumors to be deconstructed into their constituent parts and then reassembled in culture with either total immune and fibroblastic stroma or through selective incorporation of molecularly defined stromal cell populations. These assays from a platform to identify new cancer targets and to test candidate therapeutic compounds in a systematic fashion.