Lineage- and species-specific sensitivity or resistance to cancer - Insights from RB loss and KRAS activation

It is known but poorly understood why the common effect of “oncogenic” mutations is not cancer.  Lineages that are cancer-prone are far outweighed by those that are cancer-resistant.  On another level, cancer susceptibility of orthologous lineages is also species-specific. For example, human RB null cone photoreceptor precursors are cancer-prone, but cancer resistant in other mammals.  We have deduced the underlying molecular network explaining this difference, generating the first cone-derived murine model of retinoblastoma.  As well as species specificity, RB mutation also provides striking examples of lineage specific susceptibility to transformation. Why one lineage is cancer-prone and another cancer resistant is unknown.  We uncovered a hallmark of lineage-specific susceptibility to RB loss. Remarkably, a tissue can exhibit numerous hallmarks of mature cancer, but if the initiation hallmark is not present, the tissue remains cancer-free. In lung, RB loss or KRAS activation render distinct lineages cancer-prone.  Our cancer initiation hallmark predicts the cancer-prone lineage in both scenarios.  Together our work provides insight into species and lineage specific resistance or susceptibility to neoplastic transformation, raising new strategies for therapeutic intervention.