Small cell lung cancer (SCLC) is a highly aggressive and lethal neoplasm. To identify candidate tumor suppressors we applied CRISPR/Cas9 gene inactivation screens to a cellular model of early-stage SCLC. Among the top hits was MAX, the obligate heterodimerization partner for MYC family proteins that is mutated in human SCLC. Max deletion increases growth and transformation in cells and dramatically accelerates SCLC progression in an Rb1/Trp53-deleted mouse model. In contrast, deletion of Max abrogates tumorigenesis in MYCL-overexpressing SCLC. Max deletion in SCLC resulted in derepression of metabolic genes involved in serine and one-carbon metabolism. By increasing serine biosynthesis, Max-deleted cells exhibit resistance to serine depletion. Thus, Max loss results in metabolic rewiring and context-specific tumor suppression.

小细胞肺癌（SCLC）是一种高度侵袭性和致命性的肿瘤。为了鉴定候选肿瘤抑制因子，我们将 CRISPR/Cas9 基因失活筛选应用于早期 SCLC 的细胞模型。最热门的是 MAX，它是在人类 SCLC 中发生突变的 MYC 家族蛋白的专性异二聚化伙伴。在Rb1/Trp53缺失的小鼠模型中， Max缺失会增加细胞的生长和转化，并显着加速 SCLC 的进展。相反，在 MYCL 过表达的 SCLC 中，Max的缺失会消除肿瘤发生。SCLC 中的Max缺失导致参与丝氨酸和一碳代谢的代谢基因去抑制。通过增加丝氨酸生物合成，Max缺失的细胞表现出对丝氨酸耗竭的抵抗力。因此，Max损失会导致代谢重新布线和特定环境下的肿瘤抑制。