Cancer cells are notoriously versatile survivors that exploit normal cellular machinery to their advantage. Weizmann Institute scientists have recently identified a clever “trick” employed by these cells: Apparently, in many of their survival strategies, cancer cells “derail” a particular mechanism that is crucial to the cell’s functioning. Understanding how such derailment is accomplished could lead to new cancer therapies and help to overcome resistance to existing cancer drugs.
The mechanism in question, called endocytosis, serves to introduce substances into the cell: First, the cell’s membrane deforms to create a deep dent, like that in the surface of a rubber ball when it’s pressed with a finger. This dent expands and closes in on itself just underneath the cell membrane, forming a bubble that detaches and is transported to various locations inside the cell. A substance enclosed within the bubble – for example, a nutrient or a receptor molecule – can move in this manner from the cell’s surface into its interior. Ultimately, most substances transported in such bubbles are recycled or destroyed in an organelle called the lysosome.
Research by Prof. Yosef Yarden of the Weizmann Institute’s Biological Regulation Department, together with his former graduate student Dr. Yaron Mosesson and other colleagues at Weizmann and elsewhere, suggests that derailed endocytosis facilitates cancer development at different stages. For example, when the inner lining of the lungs or milk ducts is undergoing renewal, endocytosis periodically eliminates the receptors for growth-stimulating molecules, called growth factors, on the cell’s surface. These receptors are sucked into a bubble to be destroyed inside the lysosome, preventing abnormal cellular growth. But if endocytosis is deficient, these receptors can turn into cancer-causing machines: They continue to convey growth signals, leading to carcinoma of the lung, breast or other organs. Overly active endocytosis, on the other hand, can also lead to cancer by destroying the molecular “glue” that holds cells together and prevents them from proliferating excessively. Likewise, in metastasis – the deadly spread of cancer throughout the body – abnormal endocytosis plays an important role: It eliminates the cancer cells’ attachment to tissues, allowing them to migrate and spread.
But how exactly is endocytosis derailed? In a study published in Developmental Cell, Mosesson and other members of Yarden’s team, in collaboration with Tel Aviv University, the Technion – Israel Institute of Technology and the University of Porto in Portugal, have identified a previously unknown component of endocytosis in human beings. The molecule, a protein called Lst2, facilitates the endocytosis of growth factor receptors. When Lst2 is lacking, these receptors fail to complete the process, getting trapped in a cancer-promoting routine: They evade the lysosome and move back to the cell surface, where they can start another cycle of growth.
A better understanding of endocytosis might help develop new drugs that would block cancer at various stages. Such understanding could also help improve the penetration of existing drugs into malignant cells, thereby overcoming tumor resistance to certain forms of chemotherapy.
Prof. Yosef Yarden’s research is supported by the M.D. Moross Institute for Cancer Research; the Aharon Katzir-Katchalsky Center; the Goldhirsh Foundation; and the estate of Benjamin Bernstein. Prof. Yarden is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology.